1. Field of the Invention
The present invention relates to novel cephalosporin antibiotics and their methods of production and use. These compounds are expected to exhibit antibiotic activity against a wide spectrum of organisms, including organisms which are resistant to conventional .beta.-lactam antibiotics.
2. Review of the Background Art
The following review of the background of the invention is merely provided to aid in the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.
Over the past three decades a large variety of antibiotics have become available for clinical use. One class of antibiotics which has seen remarkable growth are the cephalosporins, over 70 of which have entered clinical use for the treatment of bacterial infections in mammals since 1965. The cephalosporins exhibit their antibacterial activity by inhibiting bacterial peptidoglycan biosynthesis, and have been extremely effective in treating a wide variety of bacterial infections. Cephalosporins that are said to have antibacterial activity are described in U.S. Pat. Nos. 3,992,377 and 4,256,739.
Unfortunately, the wide-spread and indiscriminant use of these antibiotics has led to a rapid increase in the number of bacterial strains which are resistant to these compounds. Most importantly, this resistance has emerged among clinically important microorganisms which threaten to limit the utility of presently available cephalosporin antibiotics. In particular, resistant strains of Salmonella, S. pneumoni.ae butted., Enterobacteriace.ae butted., and Pseudomonas have emerged which threaten to undo many of the strides made in reducing mortality and morbidity from bacterial infections.
Bacterial resistance to cephalosporins follows three major pathways: (a) the development of .beta.-lactamases capable of inactivating the .beta.-lactam ring of the cephalosporin; (b) decreased cephalosporin penetration into the bacteria due to changes in bacterial cell wall composition; and (c) poor binding to penicillin-binding proteins (PBPs). The latter pathway is especially important, as the binding of .beta.-lactams to PBPs is essential for inhibiting bacterial cell-wall biosynthesis. Certain Gram-positive bacteria, namely methicillin-resistant Staphyloccus aureus ("MRSA") and enterococci are highly resistant to .beta.-lactam antibiotics. Resistance in MRSA is due to the presence of high levels of an unusual PBP, PBP2a, which is insensitive, or binds poorly, to .beta.-lactam antibiotics. The activity of .beta.-lactam antibiotics against PBP2a-containing organisms has been shown to correlate well with the binding affinity of the antibiotic to PBP2a. Currently, the glycopeptides vancomycin and teicoplanin are primarily used for MRSA bacteremia. The quinolone antibacterials and some carbapenems, such as imipenem, have been reported to be active against a few MRSA strains, but their use is restricted due to emerging resistant MRSA strains.
Experimental compounds which may possess utility as anti-MRSA or anti-enterococcal bactericides include the glycylcyclines (see. e.g., P.-E. Sum et al., J. Med. Chem., 37, (1994)), FK-037 (see. e.g., H. Ohki et al., J. Antibiotics, 46:359-361 (1993)), RP-59,500 (see. e.g., S. K. Spangler et al., Antimicro. Agents Chemother., 36:856-9 (1992)), the everninomycin complex (see, e.g., W. E. Sanders et al., Antimicro. Agents Chemother., 6: 232-8 (1974)), the 2-(biaryl)carbapenems (see. e.g., U.S. Pat. No. 5,025,006), 3-(benzothiazolylthio)cephems (see. e.g., EP Application No. 527686), 3-(thiazolylthio)carbacephems (see. e.g., R. J. Ternansky et al., J. Med. Chem., 36:1971 (1993) and U.S. Pat. No. 5,077,287) and arbekacin (S. Kondo, et al. J. Antibiotics 46:531 (1993).
Recent advances in the compounds, compositions and methods useful for treating infections in mammals arising from .beta.-lactam antibiotic resistant bacteria are described in commonly owned International Publication WO 95/26966 and U.S. patent application Ser. No. 08/222,262, filed Apr. 1, 1994, now abandoned; 08/369,798, filed Jan. 6, 1995, now abandoned; Ser. No. 08/413,713, now U.S. Pat. No. 5,756,493, issued May 26 1998; Ser. No. 08/413,714, now U.S. Pat. No. 5,607,926, issued Mar. 4, 1997; Ser. No. 08/415,065, filed Mar. 29, 1995, now abandoned; Ser. No. 08/413,712, now U.S. Pat. No. 5,604,218, issued Feb. 18, 1997; Ser. No. 08/415,064, now U.S. Pat. No. 5,789,584, issued Aug. 4, 1998; Ser. No. 08/415,069, now U.S. Pat. No. 5,593,986 issued Jan. 14, 1997; Ser. No. 08/455,969, now U.S. Pat. No. 5,698,547, issued Dec. 16, 1997; and Ser. No. 08/457,673, now U.S. Pat. No. 5,688,786, issued Nov. 18, 1997; all of which are incorporated herein by reference in their entirety, including any drawings.